SEQUOIA: At 26 Months, Zanubrutinib Prolongs PFS 58% Over Bendamustine + Rituximab in Patients With Treatment-Naïve CLL/SLL

Zanubrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, produced prolonged progression-free survival (PFS) compared with a combination of bendamustine and rituximab (BR) among treatment-naïve patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), according to results presented Sunday.

Constantine Tam, MD, MBBS, of the Peter MacCallum Cancer Centre, Melbourne, Australia, outlined interim phase 3 findings from 2 arms of the SEQUOIA trial during the 63rd Annual American Society of Hematology (ASH) Meeting and Exposition, held in Atlanta and online.

Tam presented remotely, but beyond the masks the ASH session on CLL looked like a scene from before the pandemic, with attendees filling most of the chairs or standing in the small space at the rear of the meeting room. The results from SEQUOIA came last, and Tam began with background on the transformation of CLL treatment with the rise of B-cell receptor signaling inhibitors, notably the BTK inhibitors zanubrutinib and acalabrutinib.

He said that 2 large head-to-head trials randomized trials have shown that zanubrutinib has a reduced risk of adverse events (AEs) compared with the first-generation BTK inhibitor ibrutinib, which is approved to treat CLL. BTK inhibitors generally are associated with atrial fibrillation (AF), but this has been reduced with zanubrutinib compared with ibrutinib. In this study, 3.3% of patients in the zanubrutinib arm had an AF of any grade, vs 2.6% in the comparator arm.

Four Arms of SEQUOIA

Tam explained that the SEQUOIA trial has 4 arms, and that he was presenting interim results from arm A and arm B; both from cohort 1, in which patients are without deletion (17p). Cohort 2, with arm C and arm D, has patients with deletion (17p). All patients had untreated CLL/SLL, and Tam said 80% are over 65 years of age, with an average age of 70.

In arm A, patients received zanubrutinib 160 mg until disease progression, intolerable toxicity, or the end of the study. In arm B, patients received bendamustine 90 mg/m² on days 1 and 2, then rituximab 375 mg/m² for the first cycle, followed by 500 mg/m² for cycles 2 to 6.

From October 31, 2017, to July 22, 2019, 479 patients who met criteria for arms A and B were randomized for zanubrutinib (241 patients) or the combination of bendamustine and rituximab (238 patients). Unmated immunoglobulin heavy chain variable (IGHV) was 53.4% vs 52.4%; and del(11q) was 17.8% vs 19.3%.

Males made up the majority of both arm A (63.9%) and arm B (60.5%). In both arms, most patients were from Europe with 72.2% in Arm A and 72.3% in Arm B, 14.1% and 11.8% from North America, and 13.7% and 16.0% from Asia/Pacific.

At median follow-up of 26.2 months, PFS as determined by an independent review committee (IRC), which was the primary end point, significantly favored zanubrutinib (HR, 0.42; 95% CI, 0.28-0.63; P < .0001).

Secondary end points included safety assessments. The most common AEs besides AF included bleeding of any grade and grade 3 or higher: 45.0% and 3.8% for zanubrutinib vs 11.0% and 1.8% for BR; hypertension of any grade, 14.2% vs 10.6%; infection of any grade and grade 3 or higher, 62.1% and 16.3% vs 55.9% and 18.9%; and neutropenia of any grade and grade 3 or higher: 15.8% and 11.7% vs 56.8% and 51.1%.

Other secondary end points included:

• Estimated 24-month PFS, by the IRC, was 85.5% for zanubrutinib (95% CI, 80.1%-89.6%) vs 69.5% for BR (95% CI, 62.4%-75.5%).
• Objective response rate by IRC for zanubrutinib was 94.6% (95% CI, 91.0%-97.1%) vs 85.3% for BR (95% CI, 80.1%-89.5%).
• Complete response rate was 6.6% with zanubrutinib and 15.1% with BR.
• Estimated 24-month overall survival (OS) for zanubrutinib vs BR was 94.3% (95% CI, 90.4%-96.7%) and 94.6% (95% CI, 90.6%-96.9%).

Reporting OS is challenging, Tam explained, because patients in arm B who progressed were permitted to cross over to receive zanubrutinib; 15 patients did this and improved on the therapy. Thus, zanubrutinib’s advantage in OS might be impossible to know. In response to a question, he said, “We do know [zanubrutinib] is very reliable as a second-line agent…so there's no reason to believe that those patients didn't do well, as you’d expect.”

He said the benefits of zanubrutinib occurred “across every important prognostic subgroup,” except for a small group of patients with mutated IGHV (HR 0.67, 1-sided P = .0929).

Adverse Events

When looking at a table of common AEs such as rash, nausea, constipation, anemia, pyrexia, and thrombocytopenias, Tam noted that all were seen far less in the zanubrutinib arm.

“Looking at the more common adverse events, including nausea, as well as an increased risk of cytopenias. even look at the adverse events and special interest—once again, there's no surprises here,” he said.

More patients in the BR group stopped treatment due to AEs (31 patients, 13.7%) than in the zanubrutinib group (20 patients, 8.3%). AEs leading to death occurred in 11 patients in the zanubrutinib group (4.6%) vs 12 patients in the BR group (5.3%). No sudden deaths were reported.

In response to a question about infections, Tam revealed a remarkable point about the difference between the 2 arms: The most common infection was grade 2 upper respiratory tract infections. “We know the clinical significance of COVID is very important,” he said. As it turns out, the patients in the BR arm had completed treatment when the pandemic hit, but not so for the zanubrutinib arm. Five patients had severe infections due to COVID-19, and 4 died.

“So, there was actually a major difference in the severe infection[s],” he said.

Reference

Tam CS, Giannopoulous K, Jurczak W, et al. SEQUOIA: Results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 63rd Annual American Society of Hematology Meeting and Exposition; Atlanta, GA: December 12, 2021; Abstract 396. https://ash.confex.com/ash/2021/webprogram/Paper148457.html